Tumor Necrosis Factor-α Gene Polymorphism is Associated with Short- and Long-Term Kidney Allograft Outcomes

Felix Poppelaars; Mariana Gaya da Costa; Bernardo Faria; Siawosh K Eskandari; Marc A Seelen; Jeffrey Damman

doi:10.2147/JIR.S334738

Tumor Necrosis Factor-α Gene Polymorphism is Associated with Short- and Long-Term Kidney Allograft Outcomes

J Inflamm Res. 2022 Apr 5:15:2243-2254. doi: 10.2147/JIR.S334738. eCollection 2022.

Authors

Felix Poppelaars¹, Mariana Gaya da Costa^{1

2}, Bernardo Faria^{1

3}, Siawosh K Eskandari¹, Marc A Seelen¹, Jeffrey Damman⁴

Affiliations

¹ Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
² Department of Anesthesiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
³ Nephrology and Infectious Disease R&D Group, INEB, Institute of Investigation and Innovation in Health (i3S), University of Porto, Porto, Portugal.
⁴ Department of Pathology, Erasmus Medical Center, University Medical Center, Rotterdam, The Netherlands.

Abstract

Introduction: Kidney transplantation has excellent short-term results with current immunosuppression regimes, but long-term outcomes have barely improved over the past two decades. Hence, there is a need for new therapeutic options to increase long-term survival of kidney grafts. Drug development for kidney transplantation has slowly plateaued, limiting progress while making drug repurposing an attractive alternative. We, therefore, investigated the impact of tumor necrosis factor-alpha (TNF-α) gene (TNF) polymorphisms on kidney graft survival after transplantation.

Methods: We performed a prospective cohort study to assess the association of TNF polymorphisms (rs1800629 G>A and rs3093662 A>G) with primary non-function and death-censored kidney allograft survival in 1271 kidney transplant pairs from the University Medical Center Groningen in The Netherlands.

Results: The G-allele of the TNF rs3093662 polymorphism in donor kidneys was associated with a higher risk of immediate graft loss (odds ratio: 2.05; 95%-CI: 1.06-3.97; P = 0.032). Furthermore, the G-allele of this TNF rs3093662 polymorphism in the donor was also associated with worse 5-year, 10-year, and 15-year death-censored kidney graft survival (P < 0.05). The cumulative incidence of graft loss was 15.9% in the reference AA-genotype group and 25.2% in the AG/GG-genotype group, respectively. In multivariable analysis, the association between the TNF rs3093662 polymorphism in the donor and 15-year death-censored kidney graft survival remained significant (hazard ratio: 1.51; 95%-CI: 1.05-2.19, P = 0.028).

Discussion: In conclusion, kidney allografts possessing a high-producing TNF polymorphism have a greater risk of immediate and late graft loss. Our study adds to a growing body of literature indicating the potential of TNF-α blockade in improving kidney transplantation outcomes.

Keywords: cytokines; genetics; kidney transplantation; nephrology.

Grants and funding

This work was financially supported by the Graduate School of Medical Sciences of the University of Groningen.